The external ear consists of the external auditory canal and the auricle. Otitis externa, sometimes called swimmer's ear or an external ear infection, is a commonly used term to define the infection or inflammation of the external auditory canal and auricle. Otitis externa may affect the entire ear canal, or just a small area within the canal. Otitis externa due to infection may be caused by a variety of bacteria or fungi. In addition, viral organisms are also causative of infective otitis externa. Otitis externa may also be caused by inflammation such as from a scratch, from chemical irritants in hair spray or hair dye, or even from water. Another common cause of otitis externa is the use of earplugs or wearing hearing aids. Otitis externa also occurs in many other species in addition to human.
Acute otitis externa is primarily of bacterial origin, and is often associated with high humidity, warmer temperatures and swimming. Glands within the canal secrete a waxy exudate known as cerumen which aids in trapping air born debris as well as acidifying the epithelial surface. Such acidification minimizes the overgrowth of bacteria. However, upon exposure to copious amounts of exogenous water such as, for example, swimming, the epithelial lining may become more alkaline, leading to an increased growth and over-growth in bacteria, and the resultant inflammatory response characteristic of otitis externa. Pathogens commonly associated with acute otitis externa are Pseudomonas aeruginosa, Staphylococcus epidermides, Staphylococcus aureus, and Streptococcus pyogenes. Fungi and yeast are usually found in patients with chronic otitis externa or those who are immunocompromised. Moreover, if there are chronic skin conditions that affect the ear canal skin, such as atopic dermatitis, seborrheic dermatitis, psoriasis or abnormalities of keratin production, or if there has been a break in the skin from trauma, even the normal bacteria found in the ear canal may cause infection and full-blown symptoms of otitis externa.
Acute otitis externa occurs rather suddenly, rapidly worsens, and becomes very painful and alarming. The ear canal has an abundant nerve supply, therefore, the pain is often severe enough to interfere with sleep. Temporary deafness may also result as swelling and discharge physically close off the ear canal and prevent conduction of ambient sound to the ear drum. In more severe or untreated cases, the infection can spread to the soft tissues of the face that surround the adjacent parotid gland and the jaw joint, making chewing painful. Most bouts of otitis externa clear within a week or so with ear drops or sprays. However, in some cases the otitis externa becomes chronic (persistent). This means it lasts longer than three months. Occasionally, it can last for several years.
Chronic otitis externa is commonly caused from a fungal or allergic origin. Although not caused by as many factors, chronic otitis externa is about ten times more prevalent than acute otitis externa. Candida albicans and Aspergillus species are the most common fungal pathogens responsible for the condition. Fungal ear canal infections, also known as otomycosis, range from inconsequential to very severe. Fungus can be saprophytic, in which there are no symptoms and the fungus simply co-exists in the ear canal in a harmless parasitic relationship with the host. If for any reason the fungus begins active reproduction, the ear canal can fill with dense fungal debris, causing pressure and ever-increasing pain that is unrelenting until the fungus is removed from the canal and anti-fungal medication is used. Most antibacterial ear drops also contain a steroid to hasten resolution of canal edema and pain. However, such drops make fungal infection worse. Prolonged use of them promotes growth of fungus in the ear canal.
In the past, otitis externa has been treated with topical application of antibacterial and antifungal agents, as well as anti-inflammatory agents. Broad spectrum topically effective antibiotic otic formulations containing antibacterial agents, such as neomycin sulfate, colistin sulfate, polymyxin b, or their combinations, have been utilized to destroy causative bacteria. Anti-mycotic topically acting agents, such as nystatin and clotrimazole, have been used to destroy underlying fungal disease. In addition, the anti-viral agent acyclovir has also been utilized to treat viral based otitis externa.
Anti-inflammatory agents, often included in the above mentioned otic formulations, have been used to control the inflammatory process of otitis externa. The anti-inflammatory agents include, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate. The above described active agents are often used in combination to treat both the causative, for example, bacterial infection, as well as the inflammatory process itself. The otic formulations are often utilized in drop form for topical administration to the effected ear. In order to achieve a uniform delivery of a medication to the epithelial lining of the auditory ear canal, wicks, comprised of absorbent material such as cotton, are utilized to draw the suspensions into the ear canal.
Many otic drops also contain a topical anesthetic for immediate relief of pain caused by the infection or inflammation. However, there are disadvantages to include a topical anesthetic in the composition, because numbing the pain may mask symptoms of an advancing infection, and may hide symptoms that may cause serious if not permanent damage. Moreover, some topical anesthetics such as pramoxine is known to cause contact dermatitis or induce inflammation to an allergic response.
The macrocyclic lactones (avermectins and milbemycins) are products or chemical derivatives thereof, of soil microorganisms belonging to the genus Streptomyces. The avermectin series and milbemycin series of compounds are very potent antiparasitic agents, useful against a broad spectrum of endoparasites and ectoparasites in mammals and also having agricultural utilities against various nematode and insect parasites found in and on crops and in soil. Compounds of this group include avermectins, milbemycins, and their semi-synthetic derivatives, for example, ivermectin, doramectin, emamectin, eprinomectin, selamectin, latidectin, milbemectin, moxidectin, nemadectin, milbemycin oxime, and lepimectin. These chemicals have been described, for example, in U.S. Pat. Nos. 3,950,360, 4,199,569, 4,879,749 and 5,268,710. The avermectins and, to a lesser extent, the milbemycins, have revolutionized antiparasitic and antipest control over the past few decades.
In terms of their mechanism of action as antiparasitic agents, the avermectins block the transmittance of electrical activity in nerves and muscle cells by activating voltage dependent membrane-bound proteins containing chloride channels. Chloride channel blockers in both insects and mammals are highly toxic convulsants causing a hyperexcitation of the nervous system through antagonism of the inhibitory neurotransmitter GABA. Avermectin compounds effectively block GABA stimulated uptake and cause a release of chloride-channel dependent neurotransmitters. Milbemycin compounds have a similar mechanism of action, but a longer half-life than the avermectins. Milbemycin compounds open glutamate sensitive chloride channels in neurons and myocytes of invertebrates, leading to hyperpolarization of these cells and blocking of signal transfer.
Ivermectin has been used as an antiparasitic agent to treat various animal parasites and parasitic diseases since mid-1980's. It is commercially available for animal use as Cardomec™ (for felines), Zimecterin® (for equines) and Ivomec® (for bovines) by MERIAL Limited, Duluth, Ga. The medicine is available in tablets, paste, or chewables for heartworm prevention, topical solution for ear mite treatment, or as oral or injectable solution for other parasite problems.
Ivermectin is also commercially available from Merck & Co., Inc for human use under the tradename of Stromectol® for eradication of threadworm Strongyloides stercoralis, and for eradication of Onchocerca volvulus. The medicine is available in tablets and is orally administered by the patients. Magda et al. (Amer. J. Trop. Med. Hyg. 53(6) 1995 pp. 652-653) describe a method of topical application of ivermectin to treat head lice. U.S. Pat. No. 5,952,372 (to McDaniel) discloses a method of treating a form of rosacea associated with the ectoparasite Demodex by eliminating mites.
Recently, ivermectin has also been found useful in treating dermatological conditions. U.S. Pat. Nos. 6,133,310, 6,433,006, 6,399,652, 6,399,651 and 6,319,945 (to Parks) disclose methods of treating acne rosacea, seborrheic dermatitis, acne vulgaris, transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions by topically applying an avermectin compound, particularly ivermectin, to the affected areas.
It is also noted that the above described parasitic diseases and dermatological conditions by themselves are not the cause of otitis externa.
Because of the many causes described above, otitis externa is fairly prevalent, affecting about three to five percent of the population. Moreover, chronic otitis externa is much more prevalent than acute otitis externa. Therefore, there is a need for effective and improved otic compositions for treating otitis externa.